CHIRALITY 27:523–531 (2015)

Special Issue Article Synthesis and Properties of a Novel Pyridineoxazoline Containing Optically Active Helical Polymer as a Catalyst Ligand for Asymmetric Diels–Alder Reaction HENG WANG, NA LI, JIE ZHANG, AND XINHUA WAN* Beijing National Laboratory for Molecular Sciences, Key Laboratory of Polymer Chemistry and Physics of MOE, Center for Soft Matter Science and Engineering, College of Chemistry and Molecular Engineering, Beijing, China

ABSTRACT A novel pyridineoxazoline (PyOx) containing helical polymer, poly{(–)-(S)-4-tertbutyl-2-[5-(4-tert-butylphenyl)-3-vinylpyridin-2-yl]-oxazoline} (PA), was designed and synthesized to approach the effect of chain conformation on the catalytic property. Its complex with Cu(OTf)2, i.e., Cu(II)–PA, was employed to catalyze the homogeneous Diels–Alder (D–A) reaction of alkenoyl pyridine N-oxides with cyclopentadiene in tetrahydrofuran. Compared with the previously reported copper complex, Cu(II)–P1 (RSC Advances, 2015, 5, 2882), which was derived from a nonhelical poly[(–)-(S)-4-tert-butyl-2-(3-vinylpyridin-2-yl)-oxazoline], Cu(II)–PA exhibited a remarkably enhanced enantioselectivity and reaction rate. However, its enantioselectivity was lower than the Cu(II) complex of (–)-(S)-4-tert-butyl-2-[5-(4-tert-butylphenyl)-3-vinylpyridin-2-yl]oxazoline (Cu(II)–A), a low molar mass model compound. Chirality 27:523–531, 2015. © 2015 Wiley Periodicals, Inc.

KEY WORDS: radical polymerization; chiral induction; enantiomer excess; optical active helical polymer–copper(II) complex; polymer based catalysis

Asymmetric catalysis, playing key roles in producing enantiomerically pure compounds, has attracted great attention in the past decades and has been the heart of contemporary organic chemistry.1–3 Enzymes are the particularly efficient natural polymeric asymmetric catalysts, which provide the substratespecific chiral reaction environments.4,5 Helical conformation, which is one of the most common chiral structures in proteins and peptides of enzymes, plays vital roles in the enantioselection of target products.6–9 However, the application of enzymes in organic synthesis meets some problems, in particular the limited resources of enzymes, relatively narrow substrate scope, and insufficient stability in organic solvents.10,11 Artificial helical polymers possessing well-organized catalytic sites may act as enzymes in asymmetric catalysis, but are outstanding for their facile preparation and tolerability of organic solvents. Until now, many categories of synthetic helical polymers have been available, such as poly(methacrylate)s,12 poly(acetylene)s,13–15 poly (isocyanide)s,16,17 poly(isocyanate)s,18,19 polyguanidines,20–22 polysilanes,23–25 and poly(vinylterphenyl)s.26–34 Some of them have demonstrated potential uses in asymmetric catalysis. Reggelin and co-workers developed pyridine derived poly (tritylmethacrylate)s to catalyze asymmetric allylic substitution of 1,3-diphenylprop-2-enyl acetate and allylation of benzaldehyde.35–37 Yashima and co-workers applied cinchona alkaloid tethered poly(phenylacetylene)s in asymmetric Henry reaction of aldehyde with nitromethane.38 Pu and co-workers utilized chiral polybinaphthols in promoting asymmetric addition reaction of aldehydes with diethylzinc.39 And Suginome and co-workers used phosphine-palladium(II) complex bonded polyquinoxaline in asymmetric hydrosilylation of styrene and asymmetric silaboration of meso-methylenecyclopropanes.40–42 These pioneering works have significant meanings in practical © 2015 Wiley Periodicals, Inc.

applications and fundamental research, especially inspiring the efforts to mimic the functions of enzymes in asymmetric catalysis with optically active helical polymers as either organic catalysts or chiral ligands of organometallic catalysts. Bis(oxazoline) (BOX) and its derivatives are among the most successful ligands of organometallic catalysts in catalyzing a great amount of asymmetric reactions with excellent yields and enantioselectivities.43 Its Cu(II) complex was first used as a catalyst in asymmetric Diels–Alder (D–A) transformation of acrylate imide with cyclopentadiene by Evans and co-workers, which afforded the adduct in good yield (>80%) and over 98% enantiomeric excess (ee).44 Thereafter, a series of works were reported on modifying the chemical structures of BOX ligands,43,45 changing the metal,46,47 and alternating the substrates.48,49 The immobilization of BOX to polymers,50 i.e., polyethylene glycol,51–53 linear polystyrene54–56 or cross-linked polystyrene,57–60 has been fully developed to recycle the catalyst. Mono(oxazoline) inherits most of the advantages of BOX,61 but is easier to prepare and consumes a less amount of chiral agents.62–64 Pyridineoxazoline (PyOx) acted as a bidentate ligand and has robust complexation ability with various kinds of metal ions.61 Its metal complex has excellent enantioselectivity in catalyzing allylic alkylation reaction,65,66 Heck type reactions,67,68 and Wacker-type cyclizations.69,70 However, few reports were concerned about utilizing the metal complex of *Correspondence to: Xinhua Wan, Peking University, Chengfu Road 202, Haidian District, Beijing, 100871, China. E-mail: [email protected] Received for publication 14 February 2015; Accepted 20 March 2015 DOI: 10.1002/chir.22448 Published online 23 April 2015 in Wiley Online Library (wileyonlinelibrary.com).

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PyOx in an asymmetric D–A reaction, probably due to its less bulky geometry and lack of C2 asymmetric axis.48 Several works reported on tethering PyOx-metal complex to polymer backbone, but none of them were applied in a D–A reaction.71,72 Martinez-Merino et al. introduced the PyOx group onto polystyrene resin, whose Cu(II) complex was used in asymmetric cyclopropanation of styrene with an enhancement in enantioselectivity than the smaller molar mass counterpart.55 In our previous work, a soluble and recyclable PyOx-Cu(II) containing chiral polymeric organometallic catalyst and its low molar mass model compound (Chart 1) were developed.73 They were utilized in catalyzing the asymmetric D– A reaction, in which the polymeric catalyst yielded the products with a much higher reaction rate and enantioselectivity. These results were rationalized by the constrained environment around the catalytic site provided by the polymer backbone. P1 and its Cu(II) complex did not form helical conformation, probably because of the less bulky side groups. Herein, we aimed to develop a PyOx containing polymeric ligand, which possessed a stable helical conformation in solution. Coupling with bulky p-tert-phenyl group, a novel monomer, (–)-(S)-4-tert-butyl-2-[5-(4-tert-butylphenyl)-3-vinylpyridin-2-yl]-oxazoline was synthesized, and its polymer was prepared by free radical polymerization. The catalytic complexes were obtained via the coordinations of the polymer or monomer with Cu(OTf)2. The polymer and its Cu(II) complex proved to take a prevailing helical conformation in terms of optical rotation and circular dichroism (CD) spectrometry. The two complexes were utilized in asymmetric D–A transformation of several alkenoyl pyridine N-oxides with cyclopentadiene, respectively. Compared with the results reported in the previous work, these two novel catalysts gave the product with 10 ~ 20% enhancement in enantioselectivity. However, unexpectedly, the helical conformation of the polymeric catalyst was not efficiently enhanced in the enantioselectivity of the reactions. MATERIALS AND METHODS Materials 2,5-Dibromo-3-methylpyridine (97%, Heowns Biochem Technology, Beijing, China), cuprous cyanide (CuCN, AR, Beijing Chemical Co., Beijing, China), tetrachloromethane (CCl4, AR, Beijing Chemical Co.), Nbromosuccinimide (NBS, 99%, Aldrich, St. Louis, MO), triphenylphosphine (PPh3, 99%, Acros, Somerville, NJ), aqueous formaldehyde (40%, AR, Beijing Chemical Co.), 4-tert-butylphenylboronic acid (98%, J&K Scientific, Beijing, China), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)3, 99%, Acros), (S)-tert-leucinol (97%, TCI Co.), zinc(II) triflate (Zn(OTf)2, 98%, J&K Scientific), copper(II) triflate (Cu(OTf)2, 98%, J&K Scientific), and 2,6-di-tert-butyl-4-methylphenol (BHT, 98%, J&K Scientific) were used as purchased. Azobisisobutyronitrile (AIBN, AR, Wuhan Chemical Co.) was recrystallized from ethanol and dried under vacuum at room temperature. Tetrahydrofuran (THF, AR, Beijing Chemical Co.) was refluxed with sodium and distilled out just before use. Dimethylforamide (DMF, AR, Beijing Chemical Co.) was refluxed with calcium hydride.

Chart 1. Chemical structures of PyOx-Cu(II) containing polymeric organometallic catalyst, Cu(II)–P1, and its low molar mass counterpart, Cu(II)–3. Chirality DOI 10.1002/chir

Cyclopentadiene was freshly cracked and distilled from its dimer. The substrates 2-alkenoyl pyridine N-oxides (4a ~ d) were prepared followed the literature method.49 1

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Measurements. H-NMR (400 MHz) and C-NMR (100 MHz) spectra 1 were recorded on a Bruker (Billerica, MA) ARX400 spectrometer. HNMR (300 MHz) spectra were obtained on a Varian (Palo Alto, CA) Mercury Plus spectrometer at room temperature in CDCl3. In all cases, tetramethylsilane (TMS) was employed as an internal standard. High resolution mass spectra (HRMS) were collected on a Bruker Apex IV FTMS mass spectrometer. FT-IR spectra were collected on a Bruker Tensor 27 spectrometer at room temperature as KBr cells. The weight- and number-average molecular weights (Mw and Mn, respectively) were estimated by a gel permeation chromatography (GPC) apparatus equipped with a Waters (Milford, MA) 2410 refractive-index detector and a Water 515 pump. Three Waters Styragel columns with a 10 μm bead size were connected in series. Their effective molecular weight ranges were 100– 10,000 for Styragel HT2, 500–30,000 for Styragel HT3, and 5000–600,000 for Styragel HT4, respectively. The pore sizes were 50, 100, and 1000 nm for Styragel HT2, HT3, and HT4, respectively. THF was employed as the eluent at a flow rate of 1.0 mL/min at 35°C. All GPC curves were calibrated against a series of monodispersed polystyrene standards. Optical rotation data were collected on a JASCO Model P-1030 digital polarimeter using a water-jacketed 50 mm cell at 25°C. UV-Vis absorption spectra were determined on a Varian Cary 1E UV-Vis spectrometer. Circular dichroism (CD) spectra were recorded on a JASCO J-810 with a 10 mm quartz cell at 25°C. The temperature was mediated with a Julabo F25-Me controller. The enantiomeric excess was estimated with high-performance liquid chromatography (HPLC) equipped with a JASCO PU-2089 pump, an AS-2055 automatic sampler, a UV-2070 UV-Vis spectrometer, a CD-2095 circular dichroism spectrometer, and a Daicel CHIRALPAK AD-H column. The eluents used were the mixtures of isopropanol and hexane with the compositions of 3/97–20/80 (v/v) at a rate of 1.0 mL/min. 5-Bromo-3-methyl-picolinonitrile. 2,5-Dibromo-3-methylpyridine (58.0 g, 0.231 mol) and CuCN (20.7 g, 0.231 mol) were dissolved in 200 mL of anhydrous DMF. The mixture was heated to 120°C for 12 h. Afterwards, the mixture was poured into 1500 mL of water, and the precipitates were filtrated off and washed with fresh water and ethyl acetate. The filtrate was extracted by 3 × 200 mL portions of ethyl acetate. The organic layers were combined and dried with anhydrous Na2SO4 and filtered. The solvent was taken away under reduced pressure and the residue was purified by a silica gel column (CH2Cl2/petroleum: 1/1 (v/v) as the eluent) to give 11.5 g of product as 1 white solid. Yield: 25%. H-NMR (400 MHz, CDCl3, δ (ppm)): 2.56 (s, 3H, CH3), 7.85-7.87 (d, 1H, p-H to pyridinyl N), 8.59-8.60 (d, 1H, o-H to pyridinyl 13 N). C-NMR (100 MHz, CDCl3, δ (ppm)): 18.52, 115.82, 124.52, 132.32, 139.82, 140.56, 149.76. 5-Bromo-3-vinyl-picolinonitrile. 5-Bromo-3-methyl-picolinonitrile (9.80 g, 0.050 mol) and NBS (9.79 g, 0.055 mol) were dissolved in 100 mL of CCl4. The mixture was refluxed for 4 h. During this time, 4 × 50 mg portions of AIBN were added. After cooling the mixture to room temperature and filtrating off the suspended solids, the filtrate was concentrated under reduced pressure. The residue, which contained the monobromides as well as unreacted 5-bromo-3-methyl-picolinonitrile and the relevant dibromides, was mixed with PPh3 (13.1 g, 0.050 mmol) and acetone (120 mL). After refluxing overnight, a great amount of precipitates was formed. Triphenyl-(2-cyano-pyridin-3-yl)-methylphosphonium bromide was obtained as white solids by filtering the reaction mixture and washing the precipitate with 3 × 20 mL of fresh chilly acetone. The phosphonium bromide was dissolved in 100 mL of CH2Cl2, and then 200 mL of aqueous formaldehyde (40%) was added. The mixture was cooled to 0°C. With rapid stirring, 2 mol/L Na2CO3 aqueous solution (100 mL) was dropped slowly over 0.5 h. The mixture was stirred for another 2 h at room temperature. When the reaction was completed, the organic layer was collected. Another 2 × 150 mL portions of CH2Cl2 were used to extract the aqueous layer. The organic layers were combined and dried over anhydrous Na2SO4. The solvent was taken away under reduced pressure and the residue was purified by a silica gel column (CH2Cl2/petroleum: 1/1 (v/v) as the eluent) to give 3.3 g of product as white powders. The total yield of the three steps was

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31%. H-NMR (400 MHz, CDCl3, δ (ppm)): 5.72-5.77 (d, 1H, =CH2), 6.006.07 (d, 1H, =CH2), 6.97-7.06 (dd, 1H, -CH=), 8.12-8.14 (d, 1H, p-H to 13 pyridinyl N), 8.63-8.64 (d, 1H, o-H to pyridinyl N). C-NMR (100 MHz, CDCl3, δ (ppm)): 115.54, 122.64, 124.90, 129.36, 120.23, 135.50, 138.42, 151.06. HRMS m/z = 208.97142, 210.96929 (MH+), C8H6BrN2 required 208.9714, 210.9694. 5-(4-tert-Butylphenyl)-3-vinyl-picolinonitrile. To a degassed mixture of 5bromo-3-vinyl-picolinonitrile (2.30 g, 11.0 mmol), 4-tert-butylphenylboronic acid (2.20 g, 12.0 mmol), Pd(PPh3)4 (0.60 g, 0.52 mmol), and BHT (0.11 g, 0.50 mmol) were added into a solution containing benzene (50 mL), ethanol (40 mL), and aqueous Na2CO3 aqueous solution (2 mol/L, 200 mL) under a continuous stream of nitrogen. The solution was vigorously stirred at reflux until full conversion of 5-bromo-3-vinylpicolinonitrile monitored by thin-layer chromatography (TLC). Afterward, the organic layer was separated and dried over anhydrous Na2SO4. The solvent was taken away under vacuum and the residue was purified by a silica gel column (CH2Cl2/petroleum: 1/1 (v/v) as the eluent) to af1 ford 2.56 of product as colorless liquid. Yield: 89%. H-NMR (400 MHz, CDCl3, δ (ppm)): 1.38 (s, 9H, Ph-C(CH3)3), 5.68-5.74 (d, 1H, =CH2), 6.03-6.11 (d, 1H, =CH2), 7.08-7.17 (dd, 1H, -CH=), 7.52-7.58 (m, 4H, H of phenyl group), 8.07-8.11 (d, 1H, p-H to pyridinyl N), 8.78-8.82 (d, 1H, o13 H to pyridinyl N). C-NMR (100 MHz, CDCl3, δ (ppm)): 31.24, 34.79, 116.32, 121.17, 126.43, 127.06, 130.22, 130.56, 130.59, 133.03, 137.14, 139.71, 148.46, 152.89. HRMS m/z = 263.15466 (MH+), C18H19N2 required 263.1548. (–)-(S)-4-tert-Butyl-2-[5-(4-tert-butylphenyl)-3-vinylpyridin-2-yl]-oxazoline (A). Zn(OTf)2 (0.55 g, 1.5 mmol), contained in a dry three-necked flask, was heated at 90°C under vacuum for 1 h. Afterwards, the solution of (S)tert-leucinol (0.89 g, 7.6 mmol), 5-(4-tert-butylphenyl)-3-vinylpicolinonitrile (2.00 g, 7.62 mmol) and BHT (22 mg, 0.1 mmol) dissolved in 60 mL of toluene was cannulated into the flask. After refluxing for 24 h and removal of solvent under vacuum, the residue was dissolved in 100 mL of CH2Cl2 and washed with 3 × 100 mL portions of water. The organic phase was combined and dried over anhydrous Na2SO4. The solvent was taken away under reduced pressure and the residue was purified by silica gel column (CH2Cl2/methanol: 100/1 (v/v) as eluent) to obtain 0.98 g of 1 product as colorless oil. Yield: 35%. H-NMR (400 MHz, CDCl3, δ (ppm)) 1.00 (s, 9H, -C(CH3)3), 1.37 (s, 9H, Ph-C(CH3)3), 4.18-4.32 (m, 2H, -CH2-), 4.40-4.47 (m, 1H, -NCH-), 5.44-5.51 (d, 1H, =CH2), 5.76-5.84 (d, 1H, =CH2), 7.48-7.62 (m, 4H, H in phenyl group), 7.69-7.81 (dd, 1H, -CH=), 8.06-8.12 (d, 1H, p-H to pyridinyl N), 8.78-8.84 (d, 1H, o-H to pyridinyl N). 13 C-NMR (100 MHz, CDCl3, δ (ppm)): 26.03, 31.28, 34.02, 34.71, 68.50, 77.55, 117.74, 126.19, 126.97, 132.39, 134.01, 134.13, 134.61, 137.83, 142.34, 146.75, 151.99, 161.95. HRMS m/z = 363.24310 (MH+), 25 C24H31N2O required 363.2436. Specific optical rotation [α]365 = –55.2°, 25 [α]589 = –16.1° (c: 1.0 mg/mL, THF). Radical polymerization. Into a glass ampule, 0.200 g (0.55 mmol) of A, 0.51 mg (0.0028 mmol) of AIBN and 1.0 g of THF (14 mmol) were added. After three freeze–pump–thaw cycles, the tube was sealed under vacuum and put into an oil bath kept at 60°C for 24 h. After polymerization, the solvent was taken away under reduced pressure, and the residue was repeatedly immersed with methanol (5 × 20 mL). During the process, precipitates were formed gradually, and were collected by filtration and dried under vacuum at 40°C for 48 h. 0.105 g of poly{(–)-(S)-4-tert-butyl2-[5-(4-tert-butylphenyl)-3-vinyl-pyridin-2-yl]-oxazoline} (PA) was ob1 tained. Yield: 51%. H-NMR (400 MHz, CDCl3, δ (ppm)) –1.0-0.76 (broad peaks, -CHCH2-, -C(CH3)3), 0.76-1.55 (broad peaks, Ph-C(CH3)3), 1.934.52 (broad peaks, -NCHCH2O-), 5.23-7.69 (broad peaks, H of phenyl group), 7.69-8.86 (broad peaks, H of pyridinyl group). GPC: 4 25 Mn = 1.29 × 10 Da, PDI = 2.04. Specific optical rotation [α]365 = –223.2°, 25 [α]589 = –33.1°(c: 1 mg/mL, THF). Complexation of PA with Cu(OTf)2. As a typical procedure, a dry Schlenk tube containing Cu(OTf)2 (109 mg, 0.3 mmol) was heated at 90°C under vacuum over 1 h. After that, 4 mL of dry THF was added to dissolve Cu(OTf)2 under N2 atmosphere. Into another dry Schlenk tube, PA (72 mg, 0.2 mmol) and 4 mL of dry THF were added. PA solution was cannulated into Cu(OTf)2 solution slowly and smoothly, and the mixture was stirred for 24 h at room temperature. After that, 8 mL of dry THF was added to the tube to dilute the solution, which was then added dropwise

into 200 mL of ether. The target complex, Cu(II)–PA, was obtained by filtration, washed with ether, and dried under vacuum at 40°C for 24 h. [PyOx]: [Cu] = 1:1 (determined by gravimetric analysis), chemical formula: C26H30CuF6N2O7S2. Calcd for C26H30CuF6N2O7S2: C, 43.12; H, 4.18; N, –1 3.87. Found: C, 43.08; H, 4.30; N, 3.74. FT-IR (neat, KBr plate, cm ): 2964, 1624, 1589, 1479, 1373, 1253, 1176, 1030, 638, 576, 520 (FT-IR of Cu(OTf)2: 25 1262, 1178, 1036, 645, 580, 521). Specific optical rotation [α]589 = –148.7° (c: 1 mg/mL, THF). Complexation of A with Cu(OTf)2. The complex Cu(II)–A was prepared as solution by mixing Cu(OTf)2 and A at a ratio of 1:1 in THF just before 25 use. Specific optical rotation [α]589 = –180.9° (c: 1 mg/mL, THF). General procedure for the catalytic enantioselective D–A reaction by Cu(II)–PA. Into a dry Schlenk tube, Cu(II)–PA (18.0 mg, containing 0.025 mmol Cu(II)) and THF (2 mL) were added under N2 atmosphere. The mixture was stirred for 2 h at room temperature until a clear solution was obtained. The substrate, 4b (67 mg, 0.25 mmol), was added and the mixture was stirred for another 0.5 h. The solution was cooled to 0°C and cyclopentadiene (0.15 mL, 1.8 mmol) was added via syringe. The reaction process was monitored by TLC. After full conversion, the solution was added into 60 mL ether and the precipitates were separated by filtration. The filtrate was evaporated under vacuum and the residue was purified by a silica gel column with ethyl acetate as the eluent. General procedure for the catalytic enantioselective D–A reaction by Cu(II)–A. Cu(OTf)2 (9.0 mg, 0.025 mmol) in a dry Schlenk tube was heated at 90°C under vacuum for 1 h. Then, A (9.1 mg, 0.025 mmol) dissolved in 2 mL of THF was added in the tube under N2 atmosphere and the mixture was stirred over 2 h at room temperature. After that, the substrate, 4b (67 mg, 0.25 mmol), was added and the mixture was stirred for another 0.5 h. The mixture was cooled to 0°C and cyclopentadiene (0.15 mL, 1.8 mmol) was added. The reaction process was monitored by TLC. After full conversion of the substrate, the solution was evaporated under vacuum and the residue was purified by a silica gel column with ethyl acetate as the eluent.

RESULTS AND DISCUSSION Synthesis

The synthetic routes of the target polymeric catalyst, Cu(II)– PA, and its low molar mass counterpart, Cu(II)-A, are shown in Scheme 1. Owing to the higher electronic deficiency of metacarbon in pyridinyl group, the bromine at 2-position of the starting material, i.e., 2,5-dibromo-3-methylpyridine, was selectively substituted by cyano group via reacting with a stoichiometric amount of cuprous cyanide. The resultant product, 5bromo-3-methyl-picolinonitrile, was first brominated by NBS in CCl4 solution, and then reacted with PPh3 to afford triphenyl-(2-cyano-pyridin-3-yl)-methylphosphonium bromide. The phosphonium bromide was converted to the vinyl intermediate, 3-vinyl-5-bromopicolinonitrile, through Wittig reaction with formaldehyde aqueous solution under an alkaline condition. Suzuki coupling of 3-vinyl-5-bromo-picolinonitrile with 4-tert-butylphenylboronic acid afforded 3-vinyl-5-(4-tertbutylphenyl)picolinonitrile, which was transformed to the monomer, (–)-(S)-4-tert-butyl-2-[5-(4-tert-butylphenyl)-3-vinylpyridin-2yl)-oxazoline (A), through condensation with (S)-tert-leucinol catalyzed by Zn(OTf)2. The structures of all the intermediates and the monomer A were thoroughly characterized by 1H/13CNMR and high-resolution mass spectrometry. All the data agreed completely with the expected structures. Radical polymerization of A was carried out in THF solution at 60°C with AIBN as the initiator. The resultant polymer, poly{(–)-(S)-4-tert-butyl-2-[5-(4-tert-butylphenyl)-3-vinylpyridin2-yl]-oxazoline} (PA), had a moderately high molecular weight (1.29 × 104 Da) and a wide molecular weight distribution (PDI: 2.04), estimated against polystyrene standards. It had excellent solubility in less polar solvents, such as THF, chloroform, Chirality DOI 10.1002/chir

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Scheme 1. Syntheses of polymeric catalyst, Cu(II)–PA, and its low molar mass counterpart, Cu(II)–A.

anisole, ether, n-hexane, and cyclohexane, but poor solubility in polar solvents, such as methanol, acetonitrile, and DMF. This is quite different from the solubility of poly{(–)-(S)-4-tert-butyl-2(3-vinylpyridin-2-yl)-oxazoline} (P1) reported in our previous work,73 probably due to the hydrophobic nature of 4-tert-phenyl group in PA. Figure 1 shows the 1H-NMR spectra of A and PA. The peaks at 5.44–5.51, 5.76–5.84, and 7.69–7.81 ppm were ascribed to the proton resonances of vinyl group of A (Fig. 1a). After polymerization, these peaks vanished, and new broad peaks at –1.0–0.76 ppm were presented (Fig. 1b), which implied the formation of polymer backbone. In addition to these variations, every sharp signal of A became weak and broad after polymerization due to the limit mobility of the protons in the stiff polymer chain.74 The target polymeric cupric complex, Cu(II)–PA, was obtained by complexation of PA with Cu(OTf)2 in THF solution, in which polymer, Cu(OTf)2, and the resultant complex had excellent solubility. In order to prepare Cu(II)–PA with a molar ratio of the PyOx group to Cu(II) ([PyOx]:[Cu]) as 1:1, excess of cupric salt was added during the complexation. Afterwards, excess unreacted Cu(OTf)2 was washed out by precipitating the complexation mixture in a large amount of ether, owing to the good solubility of Cu(OTf)2 and poor solubility of Cu(II)–PA in ether. Based on the gravimetric analysis, [PyOx]:[Cu] ratio in the obtained complex was exactly 1:1. It was also verified by elemental analysis. FT-IR spectroscopy was utilized to further prove the complex structure, shown as in Figure 2. The characteristic strong stretching Chirality DOI 10.1002/chir

C = N vibration of PyOx group in PA can be discovered at 1668 cm-1. It disappeared completely and showed up at 1624 cm-1 in the spectrum of Cu(II)–PA, suggesting the full complexation of side groups. The 44 cm-1 bathochromic shift was attributed to the coordination of Cu(II) with oxazoline group, which reduced the C = N bond strength. This shift was larger than that of P1 coordinated with Cu(II), which was 30 cm-1.73 This indicated that PA has a stronger interaction with Cu(II) than P1. In addition to the vibration shift, a few new peaks ascribed to the characteristic vibrations of Cu(OTf)2 are found at 1253, 1176, 1030, 638, 576, and 520 cm-1 in the spectrum of Cu(II)–PA, which also suggested the formation of coordinated bond between Cu(II) and side chains of PA. Chiroptical Properties

The polymer PA showed a specific optical rotation [α]25 365 of –223.2° (c: 1 mg/mL, THF), whereas that of the monomer A was –55.2°. The large variation in optical rotations between the monomer and its polymer indicated that the optical activity of PA did not solely arise from the configurational chirality of oxazoline in the side chain, but a higher chiral structure, most likely one prevailing helicity, had been formed. This speculation was further confirmed by CD measurements. As shown in Figure 3, a weak positive Cotton effects centered at 305 nm and a relatively intensive negative Cotton effects centered at 230 nm were observed in the CD spectrum of A. The polymer PA displayed a quite distinct CD pattern, showing a negative Cotton effect at 293 nm and two intense positive

SYNTHESIS AND PROPERTIES OF A NOVEL PYRIDINEOXAZOLINE

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Fig. 2. FT-IR spectra of PA, and Cu(II)–PA. All samples were characterized in solid state KBr plates.

1

Fig. 1. H-NMR spectra of A (a) and PA (b) in CDCl3 solution with TMS as an internal standard. Fig. 3. CD and UV-Vis spectra of A and PA in THF solution with a concen–4 –1 tration of 2 × 10 mol L recorded at 25°C.

Cotton effects at 257 nm and 227 nm, respectively. This indicated again that the side chains of PA were arranged in a skewed way around a dominant helical main chain. The copper complexes, Cu(II)–A and Cu(II)–PA, whose chiralities directly determined the enantioselectivity of a catalytic reaction, were characterized by polarimetry and CD, benefited from the good solubility of these complexes. Figure 4 displays the UV-Vis and CD spectra of Cu(II)–A and Cu(II)–PA. In the UV region, Cu(II)–A had three obvious absorption bands centered at 328, 262, and 225 nm, respectively. Correspondingly, its CD spectrum exhibited a negative exciton coupling type Cotton effect centered at 330 nm, a remarkably positive Cotton effect at 265 nm, and a negative Cotton effect at ~220 nm. On the contrary, the CD spectrum of Cu(II)–PA is distinct from that of Cu(II)–A, which had an intensive positive Cotton effect centered at ~230 nm and negative Cotton effects at ~330 nm, 300 nm, and 272 nm, respectively. These properties were not the same with Cu(II)–P1 and its corresponding low molar mass counterpart, which exhibited almost the same CD curves.73 This

implied the skewed arrangement of p-phenylpyridinyl groups in the side chains of Cu(II)–PA, and further proved that PA and its copper complex formed helical conformations. Both Cu(II)–PA and Cu(II)–A showed a weak absorption band in the visible region around 600 ~ 800 nm, which was assigned to the symmetric forbidden d-d* electronic transition of the cupric ion. Compared with the cupric ion absorption band of Cu(II)–A, the band of Cu(II)–PA had 50 nm redshift, probably due to the influence of polymer backbone, i.e., the more crowding environment of Cu(II)–PA enhanced conjugation. Corresponding to the absorption bands, the CD spectra of both Cu(II)–PA and Cu(II)–A showed positive Cotton effects, which indicated an asymmetric environment of the cupric ions induced by the chirality of the polymer and corresponding small molecule ligands. Noteworthy, Cu (II)–PA displayed much weaker Cotton effects, implying that the cupric ions of Cu(II)–PA were arranged in a less chiral environment. This was consistent with the fact that Cu(II)– Chirality DOI 10.1002/chir

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TABLE 1. D A reaction results of 2-alkenoyl pyridine N-oxide 4a ~ c and cyclopentadiene catalyzed by Cu(II) PA or Cu a (II) A

Fig. 4. CD and UV-Vis spectra of Cu(II)–A and Cu(II)–PA in THF solution –5 –1 with a concentration of 9 × 10 mol L recorded at 25°C.

PA had lower optical rotation than Cu(II)–A (Cu(II)–PA: [α] 25 25 365 , –148.7°; Cu(II)–A: [α]365, –180.9°) . Such a phenomenon might be due to the competition of chiral induction between the side chain and the main chain, of which the configurational chirality of PyOx induced the positive Cotton effects, whereas the conformational chirality of polymer backbone induced the negative ones. D–A Reaction

The D–A reactions of the substrates 4a ~ c with cyclopentadiene were catalyzed by Cu(II)–PA or Cu(II)–A, respectively, as shown in Scheme 2. The results are summarized in Table 1. Similar to the previous work,73 Cu(II)–PA catalyzed the D–A reactions to afford excellent diastereoselectivity over 95/5 (endo/exo) regardless the substrate, which obeyed the “endo rule.”75–79 In addition, the polymeric catalyst sped up the reaction more efficiently than the monomeric catalyst. For example, Cu(II)–PA catalyzed the full conversion of 4a within 0.5 h, while Cu(II)–A took 1 h (Entries 1 and 2, Table 1). Enantioselectivity is another vital factor to evaluate the D–A catalytic reactions. Cu(OTf)2 alone catalyzed the reaction without any enantioselectivity, but high diastereoselectivity (Entry 7, Table 1). However, without Cu(II), neither A nor PA promoted the reaction (Entries 8 and 9, Table 1). This indicated that the chirality of the ligands, A or PA, provided the induction force of the enantioselective D–A catalysis, while Cu(II) acted as the catalytic reactive center. However, unexpectedly, the enantioselectivity of the catalysis by Cu(II)– PA did not exceed that by Cu(II)–A, the low molar mass counterpart. Catalyzed by Cu(II)–PA, the major

Entry

Sub.

Cat.

Time (h)

1 2 3 4 5 6 7 8 9

4a 4a 4b 4b 4c 4c 4a 4a 4a

Cu(II)-PA Cu(II)-A Cu(II)-PA Cu(II)-A Cu(II)-PA Cu(II)-A Cu(OTf)2 PA A

0.5 1 0.2 0.5 2 5 5 72 72

endo/ c exo

ee endo (%)

96 91 98 94 98 91 90 Null Null

98:2 98:2 96:4 97:3 98:2 98:2 97:3 n. d. n. d.

51.3 55.5 50.5 60.0 62.3 65.5 0 n. d. n. d.

a All experiments were carried out under nitrogen, dienophile (0.25 mmol), Cu (OTf)2 (0.025 mmol), A (0.025 mmol), or Cu(II)-PA (0.025 mmol), cyclopentadiene (1.8 mmol), and THF (2 mL); full conversion in all cases monitored by TLC. b Isolated product after column separation. c Determined by HPLC using a Daicel CHIRALPAK AD-H.

diastereomers, endo-5a ~ c were obtained with ee values of 51.3%, 50.5%, and 62.3%, which were slightly lower than the results, 55.5%, 60.5%, and 60.5% respectively, catalyzed by Cu(II)–A (Entries 1 ~ 6, Table 1). These results might be consistent with the above-mentioned discussion that Cu(II) in Cu(II)–A was arranged more asymmetrically than in Cu(II)–PA, which was caused by the competition of chirality induction between the side groups and the backbone of the polymeric catalyst. And another possibility might be that the small molecule catalyst could form some kind of aggregation that helps increase its enantioselectivity, but may not be the case of the macromolecular one.80 As reported in the previous work,73 Cu(II)–P1, the polymeric catalyst with less bulky side chains, catalyzed the same reactions with 40 ~ 50% ee; and its counterpart, Cu(II)–3, gave the results around 20 ~ 40% ee. All these results were less obvious than the enantioselectivity catalyzed by Cu (II)–PA or Cu(II)–A, respectively. The enhancement in enantioselectivity might be consistent with the newly introduced bulky group, p-tert-phenyl. Unlike BOX ligand, PyOx group did not have a C2 symmetric axis. This resulted in the D–A transformation intermediate, the complex of dienophile with Cu(II)–PA or Cu(II)–A, having two configurations,81 i. e., cis- and trans-forms distinguished by the relative position of alkenoyl group and the oxazoline ring, because the ligands around Cu(II) took a square-plane configuration (Scheme 2).44 Cis-configurational intermediate reacted with cyclopentadiene to afford the enantiomer of the product obtained from the trans one.73 The reversible transformation between the two intermediate consequently caused the

Scheme 2. D–A reactions of 2-alkenoyl pyridine N-oxide 4a ~ c and cyclopentadiene. Chirality DOI 10.1002/chir

c

Yield b (%)

SYNTHESIS AND PROPERTIES OF A NOVEL PYRIDINEOXAZOLINE

Scheme 3. Proposed interaction formation between the dienophile with the ligand in the cis- or trans-configuration intermediate.

reduction of the reaction enantioselectivity. In the transition state, the size exclusion of phenyl group in the dienophile with tert-butyl group in the oxazoline ring induced the tendency to form cis-configuration intermediate and afforded enantioselective endo-adduct. Compared with Cu(II)–P1 or Cu(II)–3, p-tert-phenyl group in the complexes of Cu(II)–PA or Cu(II)–A could form π–π stacking interaction with the phenyl group of the dienophiles 4a ~ c, which further increased the tendency to form the cis-configuration intermediate and consequently yielded higher enantioselective products. CONCLUSION

In the present work, a novel chiral bulky vinyl monomer, A, bearing PyOx group was designed and synthesized. Free radical polymerization was carried out to obtain the corresponding polymer, PA, which took a stable helical conformation with a dominant screw sense in THF solution in terms of polarimetry and CD characterizations. PA was converted to the polymeric complex, Cu(II)–PA, by the coordination with Cu (OTf)2. The obtained complex was utilized to catalyze the asymmetric D–A transformation of 2-alkenoyl pyridine Noxides with cyclopentadiene in homogeneous THF solution with excellent yield and diastereoselectivity. The polymeric catalyst exhibited a faster reaction rate but slightly lower enantioselectivity than its low molar mass counterpart. This result was probably caused by the competition of chiral induction between the side groups and the backbone of the polymeric catalyst, which was implied by the CD spectrometry of Cu (II)–PA and Cu(II)–A. Compared with the less bulky polymer complex, Cu(II)–P1, Cu(II)–PA showed obvious enhancement in reaction enantioselectivity, possibly owing to the π–π interaction between the ligand and the dienophile in the intermediate. Increasing the stereoregularity of polymer main chain by employing anionic polymerization to obtain polymer ligand may improve enantioselectivity. The corresponding work is currently under development in our laboratory. ACKNOWLEDGMENTS

The financial support of the National Natural Science Foundation of China (No. 21274003) and the Research Fund for Doctoral Program of Higher Education of MOE (No. 20110001110084) are greatly appreciated. LITERATURE CITED 1. Jacobsen EN, Pfaltz A, Yamamoto H. Comprehensive asymmetric catalysis. Springer: New York; 1999. 2. Mikami K, Lautens M (Eds). New frontiers in asymmetric catalysis. John Wiley & Sons: Hoboken, NJ; 2007; 313–358. 3. Ojima I. Catalytic asymmetric synthesis. Wiley: New York; 2009.

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Chirality DOI 10.1002/chir

Synthesis and Properties of a Novel Pyridineoxazoline Containing Optically Active Helical Polymer as a Catalyst Ligand for Asymmetric Diels-Alder Reaction.

A novel pyridineoxazoline (PyOx) containing helical polymer, poly{(-)-(S)-4-tert-butyl-2-[5-(4-tert-butylphenyl)-3-vinylpyridin-2-yl]-oxazoline} (PA),...
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